The Impact of Foundation Medicine Testing on Cancer Patients: A Single Academic Centre Experience.
The use of Next-Generation Sequencing (NGS) has recently allowed significant improvements in cancer treatment. Foundation Medicine
A retrospective analysis was performed on patients with solid tumors who had FM testing between May 1, 2014 and May 1, 2018. Clinical factors and outcomes were measured using descriptive statistics using Microsoft Excel
Out of 66 FM tests, eight patients (= 12%) had a direct change in therapy based on the FM tests. Identified were 285 oncogenic mutations (median 1, range 0-31); where TP53 (n = 31, 10.9%), CDKN2A (n = 19, 6.7%), KRAS (n = 16, 5.6%) and APC (n = 9, 3.2%) were the most common FM mutations identified.
A small proportion of FM reports identified actionable mutations and led to direct treatment change. FM testing is expensive and a few of the identified mutations are now part of routine on-site testing. NGS testing is likely to become more widespread, but this research suggests that its true clinical impact may be restricted to a minority of patients.
Publication Date: 2021-08-13
Journal: Frontiers in oncology
Unraveling Ewing sarcoma tumorigenesis originating from patient-derived Mesenchymal Stem Cells.
Ewing sarcoma (EwS) is characterized by pathognomonic translocations, most frequently fusing EWSR1 with FLI1. An estimated 30% of EwS tumors also display genetic alterations in STAG2, TP53, or CDKN2A (SPC). Numerous attempts to develop relevant EwS models from primary human cells have been unsuccessful in faithfully recapitulating the phenotypic, transcriptomic and epigenetic features of EwS. In this study, by engineering the t(11;22)(q24;q12) translocation together with a combination of SPC mutations, we generated a wide collection of immortalized cells (EWIma cells) tolerating EWSR1-FLI1 expression from primary mesenchymal stem cells (MSC) derived from an EwS patient. Within this model, SPC alterations strongly favored EwS oncogenicity. Xenograft experiments with independent EWIma cells induced tumors and metastases in mice, which displayed bona fide features of EwS. EWIma cells presented balanced but also more complex translocation profiles mimicking chromoplexy, which is frequently observed in EwS and other cancers. Collectively, these results demonstrate that bone marrow-derived MSCs are a source of origin for EwS and also provide original experimental models to investigate Ewing sarcomagenesis.
Publication Date: 2021-08-04
Journal: Cancer research
Combined tumor epithelial and stromal histopathology with keratin 81 expression predicts prognosis for pancreatic ductal adenocarcinoma.
Development of a pragmatic pathologic classifier of pancreatic ductal adenocarcinoma (PDAC) that reflects biological behavior is needed.
The tumor epithelial and stromal features of PDAC and molecular subtype-related markers were evaluated in three independent cohorts.
In the non-neoadjuvant therapy cohort (n = 108), regarding tumor-epithelial feature, non-gland-forming type showed worse prognosis compared to gland-forming type (P < .001). For tumor-stromal feature, in gland-forming type, the prognosis was good in order of inactivated stroma-rich, stroma-poor, and activated stroma-rich (P = .027). Whereas, non-gland-forming type revealed no difference of prognosis according to tumor stroma. Of molecular subtype-related markers, keratin 81 expression was correlated with non-gland-forming type and poor prognosis (P = .005 and P = .021, respectively). Other markers (HNF1A, c-MET, and p53) showed no significant differences in prognosis. In the neoadjuvant therapy cohort (n = 68), non-gland-forming type was correlated with high residual tumor volume (≥20%) (P < .001) and gland-forming/stroma-poor type was not present. In the next-generation sequencing cohort (n = 55), non-gland-forming type was correlated with a higher number of the KRAS, TP53, CDKN2A, and SMAD4 mutations (P = .038).
Combined tumor epithelial and stromal histopathology with keratin 81 expression is suggested to be useful for predicting prognosis of PDAC.
Publication Date: 2021-07-29
Journal: Journal of hepato-biliary-pancreatic sciences
Frequent Genetic Alterations and Their Clinical Significance in Patients With Thymic Epithelial Tumors.
Thymic epithelial tumors (TETs) are relatively rare neoplasms, including thymomas (types A, AB, B1, B2, and B3) and thymic carcinomas (TCs). The current knowledge about the biological properties of TETs is limited due to their low incidence. This study aimed to detect genetic alterations in TETs using next-generation sequencing(NGS) and explore their clinical significance in survival.
Tumor tissues and clinical data were collected from 34 patients with resected TETs in the Tianjin Medical University General Hospital between January 2011 and January 2019, and 56 cancer-associated genes were analyzed. The data of 123 TETs were retrieved from TCGA, and the information on their clinical and somatic mutations was explored.
The cohort comprised 34 TETs including 17 thymomas and 17 TCs. The NGS results indicated that 73.08% of TCs+type B3 TETs and 37.50% of non-TCs+type B3 TETs each exhibited gene mutations. For patients with type B3/C, TP53 was the most frequent mutation (19.23%), followed by CDKN2A (11.54%). Similarly, in 123 TETs from the TCGA cohort, TP53 mutations were more frequent in patients with type B3/C than in patients with non-type B3/C (11.53%
Gene mutation profiles between TCs+type B3 TETs and non-TCs+type B3 TETs were significantly different. The presence of TP53 mutations was more frequent in TCs+type B3 TETs than in non-TCs+type B3 TETs, which was associated with a worse prognosis.
Publication Date: 2021-07-27
Journal: Frontiers in oncology
Genomic alterations and possible druggable mutations in carcinoma of unknown primary (CUP).
Carcinoma of Unknown Primary (CUP) is a heterogeneous and metastatic disease where the primary site of origin is undetectable. Currently, chemotherapy is the only state-of-art treatment option for CUP patients. The molecular profiling of the tumour, particularly mutation detection, offers a new treatment approach for CUP in a personalized fashion using targeted agents. We analyzed the mutation and copy number alterations profile of 1709 CUP samples deposited in the AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) cohort and explored potentially druggable mutations. We identified 52 significant mutated genes (SMGs) among CUP samples, in which 13 (25%) of SMGs were potentially targetable with either drugs are approved for the know primary tumour or undergoing clinical trials. The most variants detected were TP53 (43%), KRAS (19.90%), KMT2D (12.60%), and CDKN2A (10.30%). Additionally, using pan-cancer analysis, we found similar variants of TERT promoter in CUP and NSCLC samples, suggesting that these mutations may serve as a diagnostic marker for identifying the primary tumour in CUP. Taken together, the mutation profiling analysis of the CUP tumours may open a new way of identifying druggable targets and consequently administrating appropriate treatment in a personalized manner.
Publication Date: 2021-07-25
Journal: Scientific reports
Huaier Inhibits Proliferation, Migration, and Invasion of Cutaneous Squamous Cell Carcinoma Cells by Inhibiting the Methylation Levels of CDKN2A and TP53.
Cutaneous squamous cell carcinoma (CSCC) is a malignant tumor that originates from keratinocytes in the epidermis or appendage. Traditional Chinese medicine Huaier has anti-tumor activity in various malignancies. Little is known about the role of Huaier in CSCC. Here, we investigated the function of Huaier in CSCC. We treated CSCC cell line (SCL-1 and A431) with a series of concentration gradients of Huaier to examine the half maximal inhibitory concentration (IC50) of Huaier on SCL-1 and A431 cells. The IC50 of Huaier on growth of SCL-1 and A431 cells were 6.96 and 7.57 mg/mL, respectively. Moreover, Huaier reduced the methylation levels of CDKN2A and TP53, and enhanced the expression of CDKN2A and TP53 in SCL-1 and A431 cells in a dosage-dependent manner. The expression of DNA methyltransferase DNMT1 was severely repressed by Huaier treatment in SCL-1 and A431 cells. DNMT1 overexpression enhanced the methylation levels of CDKN2A and TP53, and suppressed the expression of CDKN2A and TP53 in Huaier-treated SCL-1 and A431 cells. Huaier treatment inhibited proliferation, migration, and invasion of SCL-1 and A431 cells. However, inhibition of CDKN2A or TP53 reversed the influence of Huaier treatment on proliferation, migration, and invasion of CSCC cells. In conclusion, our data demonstrate that Huaier inhibits proliferation, migration, and invasion of CSCC cells by regulating DNA methylation of CDKN2A and TP53, thereby attenuating the progression of CSCC. Thus, Huaier extract may act as a drug for treating CSCC.
Publication Date: 2021-07-23
Journal: Integrative cancer therapies
Identification of LIPH as an unfavorable biomarkers correlated with immune suppression or evasion in pancreatic cancer based on RNA-seq.
It is widely considered that pancreatic cancer (PC) is an immunosuppressive cancer. Immune-based therapies remain promising therapeutic strategies for PC. Overexpression of lipase H (LIPH) was reported to be related to immunity in cattle and has also been demonstrated to promote tumor progression in several tumors, but its role in pancreatic carcinogenesis remains unclear. Study on LIPH in PC might provide a new insight into the immunosuppression in PC.
The potential biological and clinical significance of LIPH was evaluated by bioinformatics analysis. We further investigated potential associations between the expression of LIPH and tumor immune infiltration using the CIBERSORT algorithm, the ESTIMAT algorithm, and single sample gene set enrichment analysis (ssGSEA).
LIPH was significantly overexpressed in tumor tissues compared with normal tissues. LIPH overexpression correlated with tumor recurrence, advanced histologic grade, and poorer overall survival (OS). Four of the most common somatic mutation, including KRAS, TP53, CDKN2A, and SMAD4, in PC were all correlated with high LIPH expression. And high LIPH expression was significantly correlated with KRAS activation and SMAD4 inactivation. Besides, LIPH expression was involved in various biological pathways such as negative regulation of cell-cell adhesion, actin cytoskeleton, EMT, angiogenesis, and signaling by MST1. And LIPH overexpression caused high infiltration of TAMs, Treg cells, and Th2/Th1, but reduced the infiltration of CD8
Our findings demonstrated that LIPH correlated with immune suppression or evasion and may function as a novel unfavorable prognostic biomarker in PC.
Publication Date: 2021-07-20
Journal: Cancer immunology, immunotherapy : CII
The germline/somatic DNA damage repair gene mutations modulate the therapeutic response in Chinese patients with advanced pancreatic ductal adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with molecular heterogeneity, inducing differences in biological behavior, and therapeutic strategy. NGS profiles of pathogenic alterations in the Chinese PDAC population are limited. We conducted a retrospective study to investigate the predictive role of DNA damage repair (DDR) mutations in precision medicine.
The NGS profiles were performed on resected tissues from 195 Chinese PDAC patients. Baseline clinical or genetic characteristics and survival status were collected. The Kaplan-Meier survival analyses were performed by the R version 3.6.1.
The main driver genes were KRAS, TP53, CDKN2A, and SMAD4. Advanced patients with KRAS mutation showed a worse OS than KRAS wild-type (p = 0.048). DDR pathogenic deficiency was identified in 30 (15.38%) of overall patients, mainly involving BRCA2 (n = 9, 4.62%), ATM (n = 8, 4.10%) and RAD50 genes (n = 3, 1.54%). No significance of OS between patients with or without DDR mutations (p = 0.88). But DDR mutation was an independent prognostic factor for survival analysis of advanced PDAC patients (p = 0.032). For DDR mutant patients, treatment with platinum-based chemotherapy (p = 0.0096) or olaparib (p = 0.018) respectively improved the overall survival. No statistical difference between tumor mutation burden (TMB) and DDR mutations was identified. Treatment of PD-1 blockades did not bring significantly improved OS to DDR-mutated patients than the naive DDR group (p = 0.14).
In this retrospective study, we showed the role of germline and somatic DDR mutation in predicting the efficacy of olaparib and platinum-based chemotherapy in Chinese patients. However, the value of DDR mutation in the prediction of hypermutation status and the sensitivity to the PD-1 blockade needed further investigation.
Publication Date: 2021-07-13
Journal: Journal of translational medicine
Genomic Analysis Revealed Mutational Traits Associated with Clinical Outcomes in Osteosarcoma.
The limited understanding of correlation between genomic features and biological behaviors has impeded the therapeutic breakthrough in osteosarcoma (OS). This study aimed to reveal the correlation of mutational and evolutionary traits with clinical outcomes.
We applied a case-based targeted and whole exome sequencing of eleven matched primary, recurrent and metastatic samples from three OS patients characterized by different clinical behaviors in local recurrence or systematic progression pattern.
Extensive OS-associated driver genes were detected including TP53, RB1, NF1, PTEN, SPEN, CDKN2A. Oncogenic signaling pathways including cell cycle, TP53, MYC, Notch, WNT, RTK-RAS and PI3K were determined. MYC amplification was observed in the patient with shortest disease-free interval. Linear, branched or mixed evolutionary models were constructed in the three OS cases. A branched evolution with limited root mutation was detected in patient with shorter survival interval. ADAM17 mutation and HEY1 amplification were identified in OS happening dedifferentiation. Signatures 21 associated with microsatellite instability (MSI) was identified in OS patient with extra-pulmonary metastases.
OS was characterized by complex genomic alterations. MYC aberration, limited root mutations, and a branched evolutionary model were observed in OS patient with relatively aggressive course. Extra-pulmonary metastases of OS might attribute to distinct mutational process pertaining to MSI. Further research in a larger number of people is needed to confirm these findings.
Publication Date: 2021-07-09
Journal: Cancer management and research
High tumour mutational burden and EGFR/MAPK pathway activation are therapeutic targets in metastatic porocarcinoma.
Eccrine porocarcinoma (EPC) is a rare skin cancer arising from the eccrine sweat glands. Due to the lack of effective therapies, metastasis is associated with a high mortality rate.
To investigate the drivers of EPC progression.
We carried out genomic and transcriptomic profiling of metastatic EPC (mEPC), validation of the observed alterations in an EPC patient-derived cell line, confirmation of relevant observations in a large patient cohort of 30 tumour tissues, and successful treatment of a patient with mEPC under the identified treatment regimens.
mEPC was characterized by a high tumour mutational burden (TMB) with an ultraviolet signature, widespread copy number alterations and gene expression changes that affected cancer-relevant cellular processes such as cell cycle regulation and proliferation, including a pathogenic TP53 (tumour protein 53) mutation, a copy number deletion in the CDKN2A (cyclin dependent kinase inhibitor 2A) region and a CTNND1/PAK1 [catenin delta 1/p21 (RAC1) activated kinase 1] gene fusion. The overexpression of EGFR (epidermal growth factor receptor), PAK1 and MAP2K1 (mitogen-activated protein kinase kinase 1; also known as MEK1) genes translated into strong protein expression and respective pathway activation in the tumour tissue. Furthermore, a patient-derived cell line was sensitive to EGFR and MEK inhibition, confirming the functional relevance of the pathway activation. Immunohistochemistry analyses in a large patient cohort showed the relevance of the observed changes to the pathogenesis of EPC. Our results indicate that mEPC should respond to immune or kinase inhibitor therapy. Indeed, the advanced disease of our index patient was controlled by EGFR-directed therapy and immune checkpoint inhibition for more than 2 years.
Molecular profiling demonstrated high TMB and EGFR/MAPK pathway activation to be novel therapeutic targets in mEPC.
Publication Date: 2021-06-30
Journal: The British journal of dermatology
Targeting the genetic landscape of oral potentially malignant disorders has the potential as a preventative strategy in oral cancer.
This study reviews the molecular landscape of oral potentially malignant disorders (OPMD). We examine the impact of tumour heterogeneity, the spectrum of driver mutations (TP53, CDKN2A, TERT, NOTCH1, AJUBA, PIK3CA, CASP8) and gene transcription on tumour progression. We comment on how some of these mutations impact cellular senescence, field cancerization and cancer stem cells. We propose that OPMD can be monitored more closely and more dynamically through the use of liquid biopsies using an appropriate biomarker of transformation. We describe new gene interactions through the use of a systems biology approach and we highlight some of the first studies to identify functional genes using CRISPR-Cas9 technology. We believe that this information has translational implications for the use of re-purposed existing drugs and/or new drug development. Further, we argue that the use of digital technology encompassing clinical and laboratory-based data will create relevant datasets for machine learning/artificial intelligence. We believe that therapeutic intervention at an early molecular premalignant stage should be an important preventative strategy to inhibit the development of oral squamous cell carcinoma and that this approach is applicable to other aerodigestive tract cancers.
Publication Date: 2021-06-18
Journal: Cancer letters
Early detection of pancreatic cancer using DNA-based molecular approaches.
Due to its poor prognosis and the late stage at which it is typically diagnosed, early detection of pancreatic cancer is a pressing clinical problem. Advances in genomic analysis of human pancreatic tissue and other biospecimens such as pancreatic cyst fluid, pancreatic juice and blood have opened the possibility of DNA-based molecular approaches for early detection of pancreatic cancer. In this Review, we discuss and focus on the pathological and molecular features of precancerous lesions of the pancreas, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm and mucinous cystic neoplasm, which are target lesions of early detection approaches. We also discuss the most prevalent genetic alterations in these precancerous lesions, including somatic mutations in the oncogenes KRAS and GNAS as well as tumour suppressor genes CDKN2A, TP53 and SMAD4. We highlight the latest discoveries related to genetic heterogeneity and multifocal neoplasia in precancerous lesions. In addition, we review specific approaches, challenges and clinically available assays for early detection of pancreatic cancer using DNA-based molecular techniques. Although detection and risk stratification of precancerous pancreatic neoplasms are difficult problems, progress in this field highlights the promise of molecular approaches for improving survival of patients with this disease.
Publication Date: 2021-06-09
Journal: Nature reviews. Gastroenterology & hepatology
The pancreatic cancer genome revisited.
Pancreatic cancer is a genetic disease, and the recurrent genetic alterations characteristic of pancreatic cancer indicate the cellular processes that are targeted for malignant transformation. In addition to somatic alterations in the most common driver genes (KRAS, CDKN2A, TP53 and SMAD4), large-scale studies have revealed major roles for genetic alterations of the SWI/SNF and COMPASS complexes, copy number alterations in GATA6 and MYC that partially define phenotypes of pancreatic cancer, and the role(s) of polyploidy and chromothripsis as factors contributing to pancreatic cancer biology and progression. Germline variants that increase the risk of pancreatic cancer continue to be discovered along with a greater appreciation of the features of pancreatic cancers with mismatch repair deficiencies and homologous recombination deficiencies that confer sensitivity to therapeutic targeting. Wild-type KRAS pancreatic cancers, some of which are driven by alternative oncogenic events affecting NRG1 or NTRK1 - for which targeted therapies exist - further underscore that pancreatic cancer is formally entering the era of precision medicine. Given the vast developments within this field, here we review the wide-ranging and most current information related to pancreatic cancer genomics with the goal of integrating this information into a unifying description of the life history of pancreatic cancer.
Publication Date: 2021-06-06
Journal: Nature reviews. Gastroenterology & hepatology
Prognostic Genetic Biomarkers Based on Oncogenic Signaling Pathways for Outcome Prediction in Patients with Oral Cavity Squamous Cell Carcinoma.
Mutational profiling of patients' tumors has suggested that the development of oral cavity squamous cell carcinoma (OCSCC) is driven by multiple genes in multiple pathways. This study aimed to examine the association between genomic alterations and clinical outcomes in patients with advanced stages OCSCC to facilitate prognostic stratification. We re-analyzed our previous whole-exome sequencing data from 165 long-term follow-ups of stages III and IV patients with OCSCC. Their frequent mutations were mapped to 10 oncogenic signaling pathways. Clinicopathological risk factors, relapse, and survival were analyzed to identify the genetic factors associated with advanced OCSCC. Frequent genetic alterations included point mutations in TP53, FAT1, NOTCH1, CASP8, CDKN2A, HRAS, PIK3CA, KMT2B (also known as MLL4), and LINC00273; amplified segments in CCND1, EGFR, CTTN, and FGFR1; and lost segments in CDKN2A, ADAM3A, and CFHR1/CFHR4. Comprehensive analysis of genetic alterations revealed that subgroups based on mutational signatures had a significant negative impact on disease-free survival (
Publication Date: 2021-06-03
Real-world utility of next-generation sequencing for targeted gene analysis and its application to treatment in lung adenocarcinoma.
This study investigated the clinical utility of next-generation sequencing (NGS) for detection of genetic alterations and its implications on treatment of lung adenocarcinoma in real-world practice.
Data were reviewed for 391 patients with lung adenocarcinoma who underwent NGS between March 2017 and October 2018. Formalin-fixed, paraffin-embedded archival samples were used for performing NGS targeting 382 genes, including all exons of 199 genes, 184 hotspots, and the partial introns of 8 genes often rearranged in cancer. Survival analysis was performed for stage IV disease.
Among the 391 patients, at least one actionable mutation was identified in 294 patients (75.2%). The most commonly mutated gene was EGFR (n = 130, 33.2%), involving EGFR exon 19 deletion (n = 48, 12.3%), L858R (n = 47, 12%), and others (n = 35, 9%), followed by KRAS (n = 48, 12.3%), ALK (n = 40, 10.2%), RET (6%), MET (3%), ROS-1 (3%), and BRAF (2%) mutations. TP53 (46.9%) and CDKN2A (12.6%) mutations were common co-mutations in patients with AMs. With a median follow-up duration of 16.8 months, median overall survival was 36.8 months in patients with stage IV disease. Patients treated with the corresponding targeted therapy for AMs based on NGS reports lived significantly longer than those not treated with such therapy (p < 0.001). After multivariate analysis, targeted therapy for AM was a significantly favorable factor for survival (AM without targeted therapy vs. AM with targeted therapy, hazard ratio 2.58, 95% confidence interval 1.57-4.25; p < 0.001).
This study revealed that AMs could be comparably detected using NGS. Based on these NGS results, a suitable targeted therapy can be selected, which may improve survival in patients with lung adenocarcinoma. This NGS-based approach is useful in real-world practice to provide guidance when selecting targeted therapy.
Publication Date: 2021-05-08
Journal: Cancer medicine
Verrucous carcinoma of the oesophagus is a genetically distinct subtype of oesophageal squamous cell carcinoma.
Oesophageal verrucous carcinoma (VSCC) is a rare and morphologically distinct type of oesophageal squamous cell carcinoma (SCC). Diagnosing VSCC on biopsy material is challenging, given the lack of significant atypia and the presence of keratinising epithelium and exophytic growth. The molecular pathogenesis of VSCC remains unclear. The aim of this study was to characterise the genomic landscape of VSCC in comparison to conventional oesophageal SCC.
Three cases of VSCC from the Brigham and Women's Hospital pathology archive were identified. Formalin-fixed, paraffin-embedded (FFPE) tumour tissue was used for p16 immunohistochemistry (IHC), high-risk human papillomavirus (HPV) in-situ mRNA hybridisation (ISH) and DNA isolation. Tumour DNA was sequenced using a targeted massively parallel sequencing assay enriched for cancer-associated genes. Three additional cases of VSCC were identified by image review of The Cancer Genome Atlas (TCGA) oesophageal SCC cohort. VSCC cases were negative for p16 IHC and high-risk HPV ISH. TP53 mutations (P < 0.001) and copy number variants (CNVs) for CDKN2A (P < 0.001), CDKN2B (P < 0.01) and CCND1 (P < 0.01) were absent in VSCC and significantly less frequent in comparison to conventional SCC. Five VSCC cases featured SMARCA4 missense mutations or in-frame deletions compared to only four of 88 conventional SCC cases (P < 0.001). VSCC featured driver mutations in PIK3CA, HRAS and GNAS. Recurrent CNVs were rare in VSCC.
VSCC is not only morphologically but also genetically distinct from conventional oesophageal SCC, featuring frequent SMARCA4 mutations and infrequent TP53 mutations or CDKN2A/B CNVs. Molecular findings may aid in establishing the challenging diagnosis of VSCC.
Publication Date: 2021-05-08
Uterine serous carcinoma.
Serous endometrial cancer represents a relative rare entity accounting for about 10% of all diagnosed endometrial cancer, but it is responsible for 40% of endometrial cancer-related deaths. Patients with serous endometrial cancer are often diagnosed at earlier disease stage, but remain at higher risk of recurrence and poorer prognosis when compared stage-for-stage with endometrioid subtype endometrial cancer. Serous endometrial cancers are characterized by marked nuclear atypia and abnormal p53 staining in immunohistochemistry. The mainstay of treatment for newly diagnosed serous endometrial cancer includes a multi-modal therapy with surgery, chemotherapy and/or radiotherapy. Unfortunately, despite these efforts, survival outcomes still remain poor. Recently, The Cancer Genome Atlas (TCGA) Research Network classified all endometrial cancer types into four categories, of which, serous endometrial cancer mostly is found within the "copy number high" group. This group is characterized by the increased cell cycle deregulation (e.g., CCNE1, MYC, PPP2R1A, PIKCA, ERBB2 and CDKN2A) and TP53 mutations (90%). To date, the combination of pembrolizumab and lenvatinib is an effective treatment modality in second-line therapy, with a response rate of 50% in advanced/recurrent serous endometrial cancer. Owing to the unfavorable outcomes of serous endometrial cancer, clinical trials are a priority. At present, ongoing studies are testing novel combinations of various targeted and immunotherapeutic agents in newly diagnosed and advanced/recurrent endometrial cancer - an important strategy for serous endometrial cancer, whereby tumors are usually p53+ and pMMR, making response to PD-1 inhibitor monotherapy unlikely. Here, the rare tumor working group (including members from the European Society of Gynecologic Oncology (ESGO), Gynecologic Cancer Intergroup (GCIG), and Japanese Gynecologic Oncology Group (JGOG)), performed a narrative review reporting on the current landscape of serous endometrial cancer and focusing on standard and emerging therapeutic options for patients affected by this difficult disease.
Publication Date: 2021-05-04
Journal: Gynecologic oncology
Serine/Threonine Kinase 11 Plays a Canonical Role in Malignant Progression of KRAS-mutant and GNAS-wild-type Intraductal Papillary Mucinous Neoplasms of the Pancreas.
We aimed to elucidate the clinicopathobiological significance of Serine/Threonine Kinase 11 (STK11) in pancreatic intraductal papillary mucinous neoplasms (IPMNs).
STK11 is a tumor suppressor involved in certain IPMNs, however, its significance is not well known.
In 184 IPMNs without Peutz-Jeghers syndrome, we analyzed expression of STK11 and phosphorylated-AMPKα in all cases, and p16, p53, SMAD4, and β-catenin in 140 cases by immunohistochemistry; and we analyzed mutations in 37 genes, including whole coding exons of STK11, CDKN2A, TP53, and SMAD4, and hotspots of KRAS, BRAF, and GNAS in 64 cases by targeted sequencing. KRAS and GNAS were additionally analyzed in 86 STK11-normal IPMNs using digital-PCR.
Consistent loss or reduction of STK11 expression was observed in 26/184 (14%) IPMNs. These STK11-aberrant IPMNs were 17/45 (38%) pancreatobiliary, 8/27 (30%) oncocytic, 1/54 (2%) gastric, and 0/58 (0%) intestinal subtypes (P = 8.5E-11), and 20/66 (30%) invasive, 6/74 (8%) high-grade, and 0/44 (0%) low-grade (P = 3.9E-06). Sixteen somatic STK11 mutations (5 frameshift, 6 nonsense, 1 splicing, and 4 missense) were detected in 15/26 STK11-aberrant IPMNs (P = 4.1E-06). All STK11-aberrant IPMNs were GNAS-wild-type and 96% of them were KRAS or BRAF-mutant. Morphologically, STK11-aberrant IPMNs presented "fern-like" arborizing papillae with thin fibrovascular core. Phosphorylated-AMPKα was downregulated in STK11-aberrant IPMNs (92%, P = 6.8E-11). Patients with STK11-aberrant IPMNs showed poorer survival than patients with STK11-normal IPMNs (P = 3.6E-04 overall; P = 6.1E-04 disease-free).
STK11 may play a canonical role in malignant progression and poor survival of patients with IPMNs. Aberrant STK11-driven phosphorylated AMPK downregulation may provide therapeutic opportunities with mTOR inhibitors/AMPK activators.
Publication Date: 2021-04-30
Journal: Annals of surgery
Histiocytic and Dendritic Cell Sarcomas of Hematopoietic Origin Share Targetable Genomic Alterations Distinct from Follicular Dendritic Cell Sarcoma.
Histiocytic and dendritic cell neoplasms are a diverse group of tumors arising from monocytic or dendritic cell lineage. Whereas the genomic features for Langerhans cell histiocytosis and Erdheim-Chester disease have been well described, other less common and often aggressive tumors in this broad category remain poorly characterized, and comparison studies across the World Health Organization diagnostic categories are lacking.
Tumor samples from a total of 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs), underwent hybridization capture with analysis of up to 406 cancer-related genes.
Among the entire cohort of 102 patients, CDKN2A mutations were most frequent across subtypes and made up 32% of cases, followed by TP53 mutations (22%). Mitogen-activated protein kinase (MAPK) pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCS (72% vs. 0%; p < .0001). In contrast, NF-κB pathway mutations were frequent in FDCSs but rare in M group histiocytoses (61% vs. 12%; p < .0001). Tumor mutational burden was significantly higher in M group histiocytoses as compared with FDCSs (median 4.0/Mb vs. 2.4/Mb; p = .012). We also describe a pediatric patient with recurrent secondary histiocytic sarcoma treated with targeted therapy and interrogated by molecular analysis to identify mechanisms of therapeutic resistance.
A total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies. Our findings highlight the potential value of molecular testing to enable precise tumor classification, identify candidate oncogenic drivers, and define personalized therapeutic options for patients with these aggressive tumors.
This study presents comprehensive genomic profiling results on 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs). MAPK pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCSs. In contrast, NF-κB pathway mutations were frequent in FDCSs but rare in M group histiocytosis. A total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies.
Publication Date: 2021-04-28
Journal: The oncologist
B Cell Receptor signaling and genetic lesions in TP53 and CDKN2A/CDKN2B cooperate in Richter Transformation.
B cell receptor (BCR) signals play a critical role in the pathogenesis of chronic lymphocytic leukemia (CLL), but their role in regulating CLL cell proliferation has still not been firmly established. Unlike normal B cells, CLL cells do not proliferate in vitro upon engagement of the BCR, suggesting that CLL cell proliferation is regulated by other signals from the microenvironment, such as those provided by Toll-like receptors or T cells. Here, we report that BCR engagement of human and murine CLL cells induces several positive regulators of the cell cycle, but simultaneously induces the negative regulators CDKN1A, CDKN2A and CDKN2B, which block cell cycle progression. We further show that introduction of genetic lesions that downregulate these cell cycle inhibitors, such as inactivating lesions in CDKN2A, CDKN2B and the CDKN1A regulator TP53, leads to more aggressive disease in a murine in vivo CLL model and spontaneous proliferation in vitro that is BCR-dependent but independent of costimulatory signals. Importantly, inactivating lesions in CDKN2A, CDKN2B and TP53 frequently co-occur in Richter syndrome, and BCR stimulation of human Richter syndrome cells with such lesions is sufficient to induce proliferation. We also show that tumor cells with combined TP53 and CDKN2A/2B abnormalities remain sensitive to BCR inhibitor treatment and are synergistically sensitive to the combination of a BCR and CDK4/6 inhibitor both in vitro and in vivo. These data provide evidence that BCR signals are directly involved in driving CLL cell proliferation and reveal a novel mechanism of Richter transformation.
Publication Date: 2021-04-27